title: CMRF35-like molecule 1 (CLM-1) regulates eosinophil homeostasis by suppressing cellular chemotaxis.
abstract: Eosinophil accumulation in health and disease is a hallmark characteristic of mucosal immunity and type 2 helper T cell (Th2) inflammation. Eotaxin-induced CCR3 (chemokine (C-C motif) receptor 3) signaling has a critical role in eosinophil chemotactic responses. Nevertheless, the expressions of immunoreceptor tyrosine-based inhibitory motif-bearing receptors such as CMRF35-like molecule-1 (CLM-1) and their ability to govern eosinophil migration are largely unknown. We now report that CLM-1 (but not CLM-8) is highly and distinctly expressed by colonic and adipose tissue eosinophils. Furthermore, Clm1⁻/⁻ mice display elevated baseline tissue eosinophilia. CLM-1 negatively regulated eotaxin-induced eosinophil responses including eosinophil chemotaxis, actin polymerization, calcium influx, and extracellular signal-regulated kinase (ERK)-1/2, but not p38 phosphorylation. Addition of CLM-1 ligand (e.g., phosphatidylserine) rendered wild-type eosinophils hypochemotactic in vitro and blockade of CLM-1/ligand interactions rendered wild-type eosinophils hyperchemotactic in vitro and in vivo in a model of allergic airway disease. Interestingly, suppression of cellular recruitment via CLM-1 was specific to eosinophils and eotaxin, as leukotriene B₄ (LTB₄)- and macrophage inflammatory protein-1α (MIP-1α)-induced eosinophil and neutrophil migration were not negatively regulated by CLM-1. Finally, peripheral blood eosinophils obtained from allergic rhinitis patients displayed elevated CLM-1/CD300f levels. These data highlight CLM-1 as a novel regulator of eosinophil homeostasis and demonstrate that eosinophil accumulation is constantly governed by CLM-1, which negatively regulates eotaxin-induced eosinophil responses.
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Moshkovits
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Shik
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Itan
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Karo-Atar
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Bernshtein
authors.affiliation: Laboratory of Allergy and Clinical Immunology, Department of Medicine, The Herbert Center of Mast Cell Disorders, Meir Medical Center, Kfar Saba, Israel.
authors.forename: A Y
authors.initials: AY
authors.lastname: Hershko
authors.affiliation: Department of Immunology, Genentech, South San Francisco, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: van Lookeren Campagne
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Munitz
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D054413:Chemokine CCL11 / Q000494:pharmacology; D054423:Chemokine CCL24 / Q000494:pharmacology; D054405:Chemokine CCL3 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D003106:Colon / Q000276:immunology / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007975:Leukotriene B4 / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism
chemical_list: C482560:CLM-1 protein, mouse; D054413:Chemokine CCL11; D054423:Chemokine CCL24; D054405:Chemokine CCL3; D008024:Ligands; D011971:Receptors, Immunologic; D007975:Leukotriene B4